The international, multi-site Colon Cancer Family Registry Cohort (CCFRC) is comprised of over 10,000 families and individuals at increased risk of colorectal and other cancers. Existing standardized data include baseline epidemiologic and follow-up questionnaires, clinical data, blood, samples, tumor blocks, comprehensive genotype data, including genome-wide association study (GWAS) data on a substantial proportion of subjects, and extensive molecular characterization of the colorectal tumors. In this application, we seek funding to support the infrastructure and expansion of this cohort with the following specific aims: Aim 1: Maintain the cohort by active follow-up of the CCFRC by: (i) systematically updating personal and family history of cancer and vital status, personal risk factors, prevalence of colorectal polyps, and treatment and cancer recurrence data through questionnaires and interviews; (ii) validating all reports of incident cancers diagnosed since baseline; and (iii) verifying all reports of death against regional and national death registries; (iv) continuing and enhancing with state-of-the-art approaches our retention of cohort participants over time. We will also maintain the existing Biospecimen Repositories and informatics functions. Aim 2: Continue to molecularly characterize the cohort to maximize information and efficiently facilitate multiple types of research by: (i) conducting standardized pathology review for all incident colorectal cancer cases diagnosed since baseline; (ii) sub typing incident colorectal cancer tumors by immunohistochemistry, BRAF, K-ras, and MLH1 promoter methylation; (iii) genotyping, where indicated, participants for known familial mutations in DNA mismatch repair genes and MYH; and (iv) genotyping all participants who have not yet been genotyped for 16 SNPs discovered and validated by GWAS. Aim 3: Enhancement of the cohort with additional clinical and behavioral data by: (i) collecting and abstracting medical records of treatment and recurrence data on population-based cases of colorectal cancer in the cohort since inception, and on all incident cases of colorectal cancer since baseline in selected centers that are able to accomplish this in a cost-effective manner; and (ii) strategically collecting colonoscopy and pathology reports of colonic polyps when possible for high-risk participants (i.e. Lynch Syndrome, Type X, and bi-allelic MYH carriers); and (iii) collecting additional behavioral data by questionnaire that will enhance retention of the cohort and facilitate the translation of CCFRC discoveries into clinical or public health practice. Aim 4: Continue to expand the use of the CCFRC and its resources through active collaborations with the larger scientific community.